HU188937B - Process for producing new 3-cepheme-4-carboxylic acid derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of 7? - [(Z) -2- (2-aminothiazol-4-yl) -2-oxyminoacetamido] -3-cephem-4-carboxylic acid derivatives of formula (I) and their pharmaceutically acceptable salts. wherein R 1 is hydrogen or lower alkyl; R2 is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio and R3 is carboxy; or R2 is a group of formula IX, R3 is a carboxylate group and Y is a hydrogen atom, a hydroxymethyl group or a carbamoyl group; and n is 2 or 3. CHrR2 (I) -1-

Description

The present invention relates to novel 3-cephem-4-carboxylic acid derivatives. The process of the present invention provides compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein

R ¹ is hydrogen or lower alkyl;

R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio and R ³ is carboxy; obsession

R ² is a group of formula IX, R ³ is a carboxylate group (-COOH ^- ) and Y is a hydrogen atom, a hydroxymethyl group or a carbamoyl group; and n is 2 or 3.

The present invention further relates to a process for the preparation of an antimicrobial pharmaceutical composition comprising as active ingredient a cephalosporin compound of the formula I or a salt thereof and an inert carrier.

The novel cephalosporin compounds of formula (I) and their pharmaceutically acceptable salts of the present invention exhibit antimicrobial activity against a broad range of microorganisms, such as Gram-positive and Gram-negative bacteria, and can be used as antimicrobial agents as animal nutrition additives or chemotherapeutic agents in warm-blooded animals and humans. agents for the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.

Preferred compounds of the present invention are those wherein R ^{1 is} hydrogen, lower alkyl such as methyl, ethyl or propyl;

R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio; and

R ³ is carboxy; or R ² is a group represented by the general formula (IX), R ³ is a carboxylate group and Y is a hydrogen atom, a hydroxymethyl group or a carbamoyl group; and n is 2 or 3.

Particularly preferred compounds of the present invention are those of formula (I)

R ¹ is hydrogen or methyl;

R ² is (1-methyl-1H-tetrazol-5-yl) thio and R ³ is carboxy; or R ² is a group of Formula IX, R ³ is a carboxylate group, and Y is a hydrogen atom, a 4- (hydroxymethyl) group, a 3- (hydroxymethyl) -onate, or

4 karbanroiI group; and n is 2 or 3 integers.

Further preferred compounds of the present invention are those having the formula (I)

R ¹ is hydrogen,

R ² is a group of Formula IX,

R ³ is a carboxylate group,

Y is hydrogen and n is 2.

The most preferred compound of the present invention is the left rotor (1), wherein

R ¹ is hydrogen,

R ² is a group of formula IX, p

R ³ is a carboxylate group,

Y is hydrogen and n is an integer of 2.

In addition, the formula (I) includes that the isomeric configuration of the oxynino group is Z (i.e., syn). Although the Z (i.e., syn) isoners produced by the process of the invention are preferred compounds and have the best biological properties, they may contain small amounts of E. (i.e., anti) isomer, which may be produced by isomerization during chemical production.

The present invention relates to a process for the preparation of cephalosporin compounds of formula I wherein (j) a compound of formula II wherein R ⁴ is a protecting group and R ¹ and n are as defined above or a reactive derivative thereof is condensed with With a compound of formula (III) or a salt thereof, wherein R ⁵ is a carboxy group or a protected carboxy group if

R ² is acetoxy or (1-methyl-1 H -tetrazof-5-yl) thio; obsession

^R5 represents a carboxylato radical if

R ² is a group of Formula IX wherein

Y is as defined above, and a compound of formula IV is prepared wherein R ¹ , R ² , R ⁴ , R ⁵ and n are as defined above and (ii) the substituent is removed.

Other means of the invention for the preparation of a cephalosporin compound of formula (Ia), wherein R ⁶ is (1-iiietil-lH-tetrazol-5-yl) thio group, or (IX) is a group of formula

R ¹ , R ³ , Y cs n are as defined above, by preparing (i) a compound of formula (V) or a salt thereof, wherein

R ⁷ is hydrogen or a protecting group,

R ¹ and n are as defined above, is reacted with a pyridine of formula (X) wherein:

Y is as defined above, or with (1-methyl-5-mercapto (j) -tctrazoyl or a salt thereof cs (ii) when R ⁷ is a protecting group, the protecting group is removed.

In the above reactions, a wide variety of amino groups commonly used in peptide chemistry can be used as R ⁴ or R ⁷ groups. Examples of such protecting groups include lower alkanoyl groups such as the phenyl group, the acetyl group and the pivaloyl group; mono-, di- or trihaloalkyl-lower alkyl groups such as chloroacetyl and trifluoroacetyl; lower alkoxycarbonyl groups such as inethoxycarbonyl, ethoxycarbonyl and tert-butoxy; substituted cs unsubstituted benzyloxycarbonyl such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl; substituted or unsubstituted above-lower alkyl groups such as p-methoxybertzyl and 3,4-dimethoxybenzyl; and di- or tri-phenyl-lower alkyl such as benzbidyl and trityl. On the other hand, when R ⁵ is a protected (III) or (IV) wherein karboxiesoport, the carboxy protecting group is a group must be one which is conventional method such as hydrolysis, acid-treatment 21

Ιδ8 937 easily removable by removal or reduction. Examples of such protecting groups include lower alkyl groups such as methyl, ethyl or tert-butyl; substituted or unsubstituted phenyl-lower alkyl such as benzyl, p-methoxybenzyl, and p-nitrobenzosyl; benzhydryl; tri-lower alkylsilyl such as trimethylsilyl; and the like. When R ⁵ is carboxy, the compound of formula (III) is preferably a salt before carrying out the condensation reaction. General (III). Suitable salts of the compound of formula (V), the compound of formula (V) and (1-methyl-5-mercapto) -tetrazole include inorganic salts such as sodium, potassium salts or organic salts such as trimethylamine, triethylamine. If the compound of general formula (11) can exist in two optical isomeric forms due to the presence of an asymmetric carbon atom in the general formula (XI), denoted by an asterisk, any of the isomers or racemic forms of the compound of general formula (II) . In the description of the process according to the invention, the compounds of formula (I), (II), (IV) or (V), where R ¹ is hydrogen, n is an integer 2, are understood to mean an isomer in which the asymmetric carbon atom is absolute configuration is S and the term "right-rotating isomer" is an isomer in which the absolute configuration of the asymmetric carbon atom is R.

The condensation reaction of the compound of formula (II) or a reactive derivative thereof with the compound of formula (III) or a salt thereof is carried out in a conventional manner. For example, the condensation reaction of the free form of a compound of formula II with a compound of formula III is carried out in the presence of a dehydrating agent and a solvent. Suitable dehydrating agents include, for example, dicyclohexylcarbodiimide, N-cyclohexyl-N'-morinoinocarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenyl'osphine and the like. Vilsmeier reagent prepared from dimethylformamide and phosphorous oxychloride, dimethylformamide and oxalyl chloride, dimethylformamide and phosgene or dimethylformamide and thionyl chloride may also be used as a dehydrating agent. The reaction is preferably carried out at a temperature of from -50 ° C to 50 ° C, more preferably from -30 ° C to 20 ° C. Dioxane, tetrahydrofuran, acetonylryl, chloroform, dichloromethane, dimethylformamide, N, N-dimethylacetamide, ethyl acetate, pyridine, acetone and water can be used as solvents.

On the other hand, the condensation reaction of the reactive derivative of the compound of formula (II) with the salt of the compound of formula (III) may be carried out in the presence or absence of an acid acceptor in a solvent. Suitable reactive derivatives of the compound of the formula II include, for example, acid halides (such as chloride, bromide), mixed acid anhydrides (such as mixed anhydrides of the compound of formula II and alkyl carbonate), active esters (such as p-nitro). -phenyl ester, 2,4-dinitrophenyl ester, succinimide ester, phthalide ester, benzthiazol ester, 2-pyrrolidon-1-yl ester, acid azide and acid amides (such as imidazole) -amide, 4-substituted-imidazolamide, triazolamide). Dioxane may be used as a solvent in the reaction for tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dimethylformamide, Ν, Ν-dimethylacetamide, ethyl acetate, pyridine, acetone and water. Examples of suitable acid scavengers include alkali metal hydroxides (such as potassium hydroxide, sodium hydroxide), alkali metal carbonates, or bicarbonates (such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxyamine, triethylamine), Ν, Ν-dialkylanilines (such as Ν, Ν-dimethylaniline, Ν, Ν-diethylaniline), pyridine or N-alkylmorpholines (such as N-methylmorpholine) . The reaction is preferably carried out at a temperature of from -50 ° C to 50 ° C, more preferably from -30 ° C to 20 ° C.

The deprotection or deprotection of the compound of formula (IV) thus prepared may be accomplished by conventional means such as hydrolysis, solvolysis, acid treatment or reduction. For example, when the protecting group R ^{4 is a} formyl group, an acetyl group, a t-butoxycarbonyl group, a benzhydryl group, or a trityl group and the carboxy group is a tert-butyl group or a benzhydryl group, the protecting group or groups can be removed. Suitable acids for this purpose include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid or hydrobromic acid, with trifluoroacetic acid being particularly preferred. The reaction may be carried out in the presence or absence of a solvent. Examples of suitable solvents are water. methanol, ethanol, acetic acid or dioxane. The reaction is preferably carried out at a temperature of -30 to 70 ° C, more preferably 0 to 30 ° C. When trifluoroacetic acid is used as the acid, the reaction is preferably carried out in the presence of anisole. When the protecting group R ^{4 is a} benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a benzyl group, a p-methoxybenzyl group or a 3,4-dimethoxybenzyl group and the carboxy group is a benzyl group, a p-methoxybenzyl group or a Removal of the p-nitrobenzyl group, the protecting group or protecting groups is accomplished by catalytic hydrogenation of the compound of formula IV with hydrogen in the presence of a catalyst. The catalytic hydrogenation is preferably carried out at a temperature of from 0 to 100 ° C, more preferably from 10 to 40 ° C, at atmospheric pressure or higher. Preferred catalysts are, for example, palladium BaCO ₃ , aluminium activated carbon and palladium on charcoal. Methanol, ethanol, tetrahydrofuran and water can be used as solvents in the reaction. Further, when the R ⁴ protecting group is a trifluoroacetyl group, a pivaloyl group, a methoxycarbonyl group, and the carboxy group is a methyl or ethyl group, the protecting group or groups may be removed by hydrolysis of the compound of general formula (IV). The hydrolysis of the compound of formula (V) is carried out in the usual manner, for example by treatment with an alkaline agent such as sodium hydroxide or potassium hydroxide or with an acid such as hydrochloric acid or hydrobromic acid. The hydrolysis is preferably carried out at a temperature of from 0 to 70 ° C, more preferably from 10 to 30 ° C. When the protecting group R ^{4 is a} chloroacetyl group, it is removed by reaction of a compound of formula IV with thiourea in a solvent. Suitable solvents for the reaction are methanol, ethanol and water. The reaction is preferably carried out at a temperature of from 20 to 80 ° C, more preferably from 40 to 80 ° C.

On the other hand, the compound of formula (V) and a salt thereof with pyridine of formula (X) or the (1-Nethyl-5-31)

188 93 7 mercapto) tetrazole or its salt is readily reacted in a solvent. As the solvent, water, dimethylformamide and Ν, Ν-dimethylacetamide may be used in the reaction which is preferably carried out at a temperature of 0 to 100 ° C, more preferably at 20 to 80 ° C. The reaction is preferably carried out in the presence of sodium iodide, potassium iodide, sodium bicarbonate or phosphate buffer. Removal of the protecting group R ⁷ from the product thus obtained can be carried out in the same manner as the deprotection of the compound of formula IV.

The starting material of formula (II) used in the process of the present invention is a compound of formula (VI) wherein:

R ⁴ is as defined above and a compound of formula (XII) wherein

X is a halogen atom, and

R ¹ and n are prepared by reaction of the above-described alkali agent (e.g. potassium carbonate) in a solvent (e.g. dimethylsulfoxide) at a temperature of from 10 ° C to 50 ° C to give the compound of formula VII, wherein

R ^1, R ⁴ and n are as defined above.

The compound of formula (VIII) is then hydrolyzed.

Alternatively, the starting compound (H) may be hydrolyzed by the compound (VI) and the resulting compound (VIII), wherein R ⁴ is as defined above, is the compound of formula (XII) wherein R *, n and X can be prepared by reaction of the above-mentioned in the presence of an acid binder (e.g. sodium hydride) at a temperature of 10-40 ° C in a solvent (e.g. dimethylsulfoxide). In addition, as mentioned above, the compound of formula (H) represents two optical isomers due to the presence of an asymmetric carbon atom (represented by an asterisk) in the group of formula (XI). If desired, these optical isomers may be separated by resolution. For example, compounds of formula H wherein R ¹ is hydrogen, Z is 2 and R ⁴ is trityl can be readily resolved into optical isomers of the racemic form of the compound of formula II and L or D-phenylalanine in a solvent. (e.g., methanol / dioxane mixture).

Diastereomeric salts are formed which can be separated into their components by selective crystallization. During selective crystallization, the less soluble diastereomer is recovered from the reaction mixture as a crystal and the more soluble diastereomer remains in solution. Preferably, the selective crystallization is carried out at a temperature of from 10 to 40 ° C.

The cephalosporin compound of formula (I) and the pharmaceutically acceptable salt thereof produced by the process of the present invention exhibit potent antimicrobial activity against a broad range of microorganisms such as Streptococcus (such as St, faecalis, St. pneumoniae), Staphylococcus (such as S. aures). , S. epidennidis), and Fseudomonas (such as Ps. aeruginosa, Ps. putida, Ps. stutzeii), and is characterized in particular by its potent antimicrobial activity against both Gram-positive and Gram-negative bacteria.

For example, 7β - ((Z) -2- (2-aminothiazol-4-yl) -2 - ((2-pyrrolidon-3-yl) oximino) acetamido) -3- (1-pyridinylmethyl) ) -3-cephem-4-carboxylate (1-isomer) and 7- (Z) -2- (2-aminothiazol-4-yl) -2 - [(1-methyl-2-pyrrolidone-3) -yl) oximino] -acetamido / 3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephene-4-carboxylic acid at 12.5 and 25 micrograms with minimal inhibitory concentration (Μ IC ) exhibits active activity against Streptococcus faecalis CN 478 (Agar dilution method, culture for 20 hours at 37 ° C), which is cefmenoxime (chemical name: 7? [(Z) -2- (2-aminothiazol-4-yl)) -2- (methoxyimino) -acetanido] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid] and Ceftazidime [chemical name: 7 | [(Z) -2- / 2-aminothiazol-4-yl) -2- / 2-carboxy-prop-2-yloxy-amino / acetamido] -3- (l-pyridinio-methyl / -3-cephem 4-carboxylate]] has a minimum inhibitory concentration of more than 100 micrograms / liter against the above microorganism 7β - / (Ζ) 2- (T-aminothiazol-4-yl) -2 - [(1-pyrrolidone- 3-yl) oxyiminoacetamido] acetamido / The activity of -3 - [(1-methyl-1 H -tetrazol-5-yl) thio] methyl] -3-cephem-4-carboxylic acid against Staphylococcus aureus 252R is also 16 times higher than that of Cefmenoxime and Ceftazidime. In addition, the compound of formula (I) and salts thereof produced by the process of the invention show potent antimicrobial activity against Bacillus (e.g. B. subtilis), Eschcricliia (e.g. E. coli), Klebsiella (e.g. K. pneumoniae). ), Enterobacter (e.g., E. aerogenes, E. cloacae) and Serratia (e.g., S. marcescens).

The cephalosporin compound (I) of the present invention may also exhibit strong antimicrobial activity against other bacterial strains such as Citrobacter, Proteus, Shigella, Hemophilus and Salmonella. Furthermore, the cephalosporin compounds of the formula (I) and their salts produced by the process of the present invention are characterized by a strong protective effect against microbial infections caused by various bacteria, such as Staphylococcus aureus and Pscudomonas aeruginosa, because they are well absorbed and they have a long-lasting therapeutic effect; high stability against various (3-lactamases produced by microorganisms, especially β-lactamase produced by Proteus vulgaris; and very low toxicity. For example, no rat was killed when SD-rats were dosed at 1000 mg for 14 days). / 3 - / (Z) -2- (2-Amino-thiazol-4-yl) -2- [2-pyrrolidone-3-yl] -oximino] -actamido / -3- (1-pyridine-methyl) - 3-cephem-4 carboxylates (1-isomer) were administered subcutaneously,

The cephalosporin compound of formula (I) obtained by the process of the invention may also be used as a medicament in free form or in salt form. Pharmaceutically acceptable salts of the compounds of formula I include, for example, non-toxic metal salts such as sodium, potassium, calcium, or aluminum salts; ammonium salts; salts with non-toxic amines such as trialkylamines (e.g., salts of trimethylamine and procaine); salts with inorganic acids such as hydrochloric acid or hydrobromic acid; salts with organic acids such as oxalic acid; etc These salts may be prepared by reacting a compound of formula (I) with a stoichiometrically equivalent amount of the appropriate alkaline or acid at room temperature in an aqueous solvent. The cephalosporin compound of formula (I) or a salt thereof may be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously). The daily dose of a compound of formula I or a salt thereof may vary widely

188,937 patients, depending on the age, weight and condition of the disease to be treated. In general, the daily dose of the compound of formula (I) or its salt is preferably 0.0020.2 g, particularly preferably 0.01-0.04 g / kg body weight. The compound of formula (I) or a salt thereof may be used in the form of a pharmaceutical composition comprising said substance and pharmaceutical carriers suitable for oral or pareutal administration. Suitable pharmaceutical carriers include gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talc, vegetable oil and other known pharmaceutical excipients. The pharmaceutical compositions may be in solid form such as tablets, coated tablets, pellets or capsules; or liquids such as solutions, suspensions or emulsions. They may be sterilized and / or contain additives such as stabilizing, wetting or emulsifying agents.

The following examples illustrate the invention. As used herein, the term "lower alkyl" refers to alkyl groups having from 1 to 4 carbon atoms.

Experiment 1 (In vitro antimicrobial activity)

The minimum inhibitory concentration (MIC, microgram / ml) of the test compound was determined using a standard agar plate dilution method (according to the standard method of the Japanese Chemotherapy Association). MuellerHinton agar medium (MHA, Nissui) was used in the experiment.

The results are summarized in Table 1.

Table 1

Test micro-organism Μ. I.C. (micrograms / ml) the compound of the invention (Fig. 1) Cefmenoxime (note 2) Ceftazidine (note 3) Staphylococcus aureus Terajima 0.78 1.56 12.5 Staphylococcus aureus 252R 25 100 100 Streptococcus faecalis CN-478 12.5 100 100 Bacillus subtilis ATCC 6633 0.2 1.56 3.13

Continuation of Table 1

Test micro-organism Μ. 1. C. (micrograms / ml) the compound of the invention (Note 1) Cefmenoxime (note 2) Ceftazidine (note 3) Klebsiella pneumoniae 5038 0.05 0.1 0.1 Enterobacter cloacae TU-680 0.05 0.1 0.2 It was not written by marcescens 7006 0.05 0.2 0.2 Pseudomonas e-uginosa 4096 0.39 6.25 0.78 Pseudomonas pt tida ATCC 12633 1.56 100 12.5

Comment:

1. 7 / J / (Z) -2- (2-Aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oximino] acetamide / -3- / 1-pyridinium : methyl 1-cephem-4-carboxylate (1 isomer)

Chemical Name 2: 70 - [(Z) -2- (2-Amino-thiazol-4-yl) -2-methoxy-indino] -acetamido] -3 - [(1-methyl-1H-tetrazole 54) - thioethyl] -3-cephem-4-carboxylic acid

3. Chemical Name: 70 - [(Z) -2- (2-Amino-thiazol-4-yl) -2- (2-carboxy-prop-2-yl-oximino) -acetamido] -3- (1-pyridinomethyl- cefém44-3-carboxylate

Experiment 11 (Protective action against mouse bacterial infection)

Ten mice weighing 20 ± 1g were used at each dose level. The mouse was infected intraperitoneally with enough bacteria to kill untreated mice after 24 hours. Each bacterium was resuspended in 6% mucin. The test compound was administered intramuscularly one hour after infection. Survival rates were determined 7 days after infection. The average effective dose [ED _s o, mg / kg] was estimated sample analysis of the test compound. The results are shown in Table 2 for the test compound Μ. 1. C (micrograms / kg) as determined by the procedure described in Experiment I.

-5188 937

Table 2 *

ED _SO (mg / kg)

examined micro-organism the compound of the invention (Fig. 1) Cefenoxime (Note 2) Ceftazidime (note 3) Staphylococcus aureus Smitli 1.71 (1.56) 5.32 (1.56) 7.85 (12.5) Esclierichia coli KC-14 0.05 (0.05) 0.16 (0.025) 0.08 (0.05) Serratia marcescens 7006 0.14 (0.05) 0.88 (0.2) 0.54 (0.2) Citrobacter freundii 916 0.06 (0.1) 0.19 (0.05) 0.15 (0.39) Enterobacter aerogcncs 816 1.37 (0.39) 23.85 (1.56) 26.38 (6.25)

Comment:

* the numerical values in parentheses for each test compound are M.I. C. (Minimum Inhibitory Concentration) (micrograms / ml).

1-3. identical to footnote in Table 1.

Example 1

1. (3.2 g) of (Z) -2- [2- (trityl-amino) -thiazol-1-yl] -2 - [[2-pyrrolidon-3-yl] oximino] -acetic acid is suspended in 60 ml of tetrahydrofuran and 27 g of 1-hydroxybenzothiazole and 1.93 g of dicyclohexylcarbodiimide are added. The reaction mixture was stirred at room temperature for 3 hours. The insoluble material is filtered off and the filtrate is evaporated to dryness in vacuo. The residue was redissolved in ethyl acetate and the solution was washed with 1% hydrochloric acid, 5% aqueous sodium bicarbonate, and water. The ethyl acetate solution was then dried and evaporated to dryness in vacuo. The residue was then purified by chromatography on silica gel (eluent: chloroform: methanol: 98.5:: 1.5). 4.3 g of tert-butyl 70 - [(Z) -2- (2- (trityl-amino) -thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) -oximino] -acetanide] -cephalospo ranate as a pale yellow powder.

135-145 ° C (dec.).

NMR (CDCl ₃ ) δ: 1.52 (9H, s), 2.02 (3H, s), 2.2-2.7 (2Ημη), 3.0-3.5 (4H, m), δ , 5-5.3 (4H, m), 5.6-6.0 (1H, m), 6.70 (1H, s), 6.9-7.5 (17H, m), 8.4 -8.7 (1H, broad).

2. For a mixture of 20 ml of trifluoroacetic acid and 1 ml of anisole, 1.0 g of tert-butyl 7 - [(Z) -2- (2-tritylamino) -thiazol-4-yl] -2 [ (2-Pyrrolidon-3-yl) -oximino] -acetamido] -cephalosporanate is added and the mixture is stirred for 20 minutes at room temperature. It is then concentrated in vacuo to remove trifluoroacetic acid. Ether was added to the residue and the resulting powder was filtered. The powder was suspended in water (10 mL) and sodium bicarbonate was added to dissolve. The solution was washed with ethyl acetate and chromatographed on a column of Amberlite XAD-2 nonionic polymeric resin using water (registered resin from Rohm and Haas Co., USA). Fractions containing the cephalosporin compound were collected and the solvent was evaporated in vacuo. Acetone was added to the residue and the resulting powdered precipitate was filtered off. 320 mg of sodium N - ((Z) -2-) 2-aminothiazol-4-yl] -2- [2-pyrrolidon-3-yl] oximinoacetamido / cephalosporanate are obtained as a colorless powder.

NMR (D10) δ: 2.10 (3H, s). 2.2-2.7 (2H, m), 3.153.85 (4H, m), 4.6-5.00 (2H, m), 5.01 (1H, t, J = 7Hz),

5.16 (1H, d, J = 5Hz), 5.77 (1H, d, J = 5Hz), 6.98 (1H, s).

Example 2

1. 4.0 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) -oximino] -acetic acid are dissolved in 30 ml of tetrahydrofuran and 10 ml of a mixture of Ν, Ν-dimethylacetamide and

1.27 g of 1-hydroxybenzazotriazole and 1.93 g of dicyclohexylcarbodiimide are added. The reaction mixture was stirred at 0-5 ° C for 2 hours and then poured into 30 ml of 15% water in Ν, Ν-dinethylacetamide-water containing 2.12 g of 7-aminocephalosporinic acid and 4 g of tri35 ethylamine. . The addition was carried out under ice-cooling. The mixture was then heated at the same temperature

Stir for 1.5 hours. The insoluble precipitate was filtered off and the filtrate was concentrated in vacuo to remove the solvent. The residue was poured into 300 ml of ice water. The mixture was adjusted to pH 8 with sodium bicarbonate, washed with ethyl acetate, then adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated to dryness in vacuo. Ether was added to the resulting residue

4c and the resulting powder is filtered. 3.1 g of 7/3 - ((Z) -2- [2-trityl-aminothiazol-4-yl] -2 - [(2-pyrrolidin-3-yl) -oximino] -acetamide / -phephalosporinic acid are obtained. .

NMR _(DMSO-d6) .delta: 2.03 (3H, s), 2.1-2.5 (2H, m), 3.0-3.7 (4H, m), 4.4 to 5, 2 (4H, m), 5.5-5.9 (1H, m),

5C 6.71 (1H, s), 7.0-7.6 (15H, m), 7.84 (1H, s), 8.80 (1H, br s), 9.50 (1H, broad) d).

2. Add 40 ml of 80% aqueous formic acid and 3.0 g of 7/5 / ((Z) -2- [2- (trityl-amino) -thiazole-4-yl] -2 - [(2-pyrrolidone) -yl (5b oximino) -acetamido / -cephalosporinic acid and stirred at room temperature for 2 hours. The insoluble precipitate was filtered off and the filtrate was evaporated to dryness in vacuo. Water was added to the residue and the aqueous mixture was neutralized with sodium bicarbonate and washed with ether. The aqueous mixture was then subjected to column chromatography on Diamon HP-20 non-ionic polymer resin (patented by Mitsubishi Chemical Industries Ltd., Japan) using water as eluent. Fractions containing the cephalosporin compound were collected and evaporated to dryness in vacuo. 1.5 g of sodium 61

188 937 µm-7/3 / (Z) -2- [2-aminothiazole! 4- (1J-2 - [[2-pyrrolidone-3-yl] oximino] acetamido) -cephalosporanate is obtained.

The physico-chemical properties of the product are the same as in the Examples 1-2. from the product of example.

Example 3

1. (3.25 g) of (Z) -2- [2- (trityl-amino) -thiazole-4 -] - 2 - [(2-pyrrolidon-3-yl) -oximino] -acetic acid is dissolved in 200 ml of tetrahydrofuran. and 3.14 g of benzhydryl-7- (3-amino-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylate) and 1.03 g of 1-hydroxybenzotriazole, and Dicyclohexylcarbodiimide (1.57 g) was added and the mixture was stirred at room temperature for 2 hours, then the insoluble precipitate was filtered off and the filtrate was evaporated to dryness in vacuo. The resulting residue was purified by chromatography on silica gel (eluent: ethyl acetate / benzene = 5: 2).

3.7 g of benzhydryl-7β - [(Z) -2- (2- (trityl-amino) -thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) -oximino] -acetamide] -3- [ (1-Methyl-1H-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylate is obtained.

122-126 ° C (dec.).

NMR (CDCl ₃ ) δ: 2.2-2.7 (2H, m), 3.0-3.5 (2H, m),

3.6-3.75 (2H, m), 3.78 (3H, s), 4.2-4.4 (2H, m), 5.03 (2H, m), 5.7-6, 05 (1H, m), 6.75 (1H, s), 6.88 (1H, s),

7.1-7.5 (27H, ni), 8.80 (1H, broad).

2. To a mixture of 10 ml of trifluoroacetic acid and 0.5 ml of anisole is added 860 mg of benzhydryl-7/3 - [(Z) -2- (2-tritylamino) -thiazol-4-yl] -2 - [/ - pyrrolidon-3-yl-oxirnino] -acetamido] 3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylate and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated in vacuo and the trifluoroacetic acid was removed. Ether was added to the residue and the residual powder was filtered off. The powdered precipitate was suspended in water and sodium bicarbonate was added to dissolve. The solution was washed with ethyl acetate and purified by column chromatography on Amberlite XAD-2 (registered trademark, Rohm and Haas Co., USA) using water as the eluent. Fractions containing the cephalosporin compound were collected and evaporated to dryness in vacuo. 0.3 g of sodium trimethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2 - [- pyrrolidon-3-yl] oximino] acetamido] -3 - [[1-methyl-1] H-tetrazol-5-yl] -thiomethyl] -3-cephem-4-carboxylate is obtained.

NMR _(DMSO-d6) He: 2.1-2.5 (2H, m), 3.1-3.5 (2H, m), 3.94 (3H, s), 4.2 to 4, Δ (2H, m), 4.6 δ, 8 (1H, m), 5.03 (1H, d, J = 5Hz), 5.5-5.8 (1H, m), 6.76 (1H , s), 7.3 (2H, broad s), 8.00 (1H, s), 9.55 (1H, broad).

Example 4

Oxalyl chloride (0.57 g) was added at -5-0 ° C with 15 ml of chloroform containing 0.35 g of dimethylformamide and the mixture was stirred at the same temperature for 15 minutes. To the mixture was then added 1.54 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2- [2-pyrrolidon-3-yl] -oximino] at -30 to -35 ° C. acetic acid, 0.3 g of triethylamine and 15 ml of chloroform are added and the mixture is stirred for 5 minutes at the same temperature. 1.82 g of 7β-amino-3- (1β-ridinomethyl) -3-cephcm-4-carboxylate dihydrochloride in 10 ml of corophon are added to the reaction mixture at -35 to 30 ° C and 4 ml of N, O-bis (trimethylsilyl) -acetamide and the mixture was stirred at the same temperature for 10 minutes and then at -30 to 10 ° C for one hour. The reaction mixture was then concentrated to dryness in vacuo and to the residue was added 80 ml of formic acid (0 ml). The aqueous mixture was stirred for 1 hour at room temperature and then 50 ml of water were added. The insoluble precipitate was filtered off and the filtrate was washed with ethyl acetate and evaporated to dryness in vacuo. The resulting residue was dissolved in water and subjected to column chromatography on a column of Dianion HP-20 (registered trademark, Mitsubishi Chemical Industries Ltd., Japan) using a non-micron polymer resin. The column was washed first with water and then eluted with 20% methanol. Fractions containing the cephalosporin compound were combined and evaporated to dryness in vacuo. To the residue is added gceton and the resulting powdered precipitate is filtered off. 0.84 g of 7β - [(Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) -oxynino] -acetamide] -3/1-pyridinomethyl / -3-cepheine (4) carboxylate is obtained.

Op.:250°C.

NMR (D ₂ O) δ: 2.2-2.7 (2H, m), 3.1-3.7 (4H, m), 4.0-5.5 (4H, m). 5.80 (1H, d, J = 5Hz), 6.92 (1H, s), 7.89.1 (511, m), [α] D = + 13.4 ° (C = 1.0, H ₂ O).

Example 5

Oxalyl chloride (1.56 g) was added at -5-0 ° C to 0.99 ml of dimethylformamide in 39 ml of chloroform and the mixture was stirred at the same temperature for 15 minutes. Thereafter, 4.23 g of (Z) -2- [2- (tritylanino) thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) oximino] acetic acid (d-isomer), A mixture of 84 g of triinctilamine and 39 ml of chloroform was added at -30 ° C. The reaction mixture was stirred at the same temperature for 5 minutes and then a solution of 76-amino-3'-pyridiniomethyl-3-cephem-4-carboxylate in chloroform was suspended in 5.0 g of cephem compound in 39 ml of chloroform and 11 ml of N prepared by the addition of -bis (trimethylsilyl) -acetamide at -30 to -10 ° C. The mixture was stirred at the same temperature for 30 minutes and then evaporated to dryness in vacuo. To the residue was added 100 ml of 80% aqueous formic acid and the aqueous mixture was stirred at room temperature for one hour. Water (100 mL) was added and the insoluble precipitate was filtered off. The filtrate was washed with ethyl acetate and evaporated to dryness in vacuo. The resulting residue was dissolved in water and subjected to column chromatography on Dianion HP-20 (registered trademark, Mitsubishi Chemical Industries Ltd., Japan) using a nonionic polymer resin. The column was washed with water and eluted with 20% aqueous methanol. Fractions containing the cephalosporin compound were combined and evaporated to dryness in vacuo. Acetone was added to the residue and the powder was filtered off. 2.14 g of 70 - [(Z) -2- (2-amino-thiazol-4-yl) -2 - [(2-pyrrolidin-3-yl) -oxynino] -acetainido] -3- Pyridinomethyl-3-cephem-4-carboxylate (d-isomer) is obtained. The right-turning isomer is another lens chain: 7/3 - [(Z2-2- / 2-aminothiazol-4-yl / 2-1 / (3R) -2-pyrrolidoyl-3-yl] oxyamino] acetamido] - 3- (1-pyridinomethyl) -3-cephem (4) carboxylate.

NMR (D 6 O) δ: 2.1-2.7 (2H, in), 3.1-3.7 (4H.m),

4.9-5.5 (4H.m), 5.79 (1H, d, J = 5Hz), 6.92 (1H, s), 7.89.1 (5H, m), [?] = 445.7 '(C = 1, H ₂ O).

-7188 937

Example 6

1. Oxalyl chloride (1.81 g) is added to 45 ml of chloroform containing 1.15 ml of dimethylformamide at -5 to 0 ° C and the mixture is stirred at the same temperature for 15 minutes. Thereafter, 4.90 g of (Z) -2- [2-tritylamino-thiazol-4-yl] -2 - [(2-pyrrolidone) -3-f] -oxyninoline acetic acid (1-isomer), 0.97 g of triethylamine and 45 ml of a solution of chloroform was added at -30 ° C to the reaction mixture. The mixture was stirred at the same temperature for 5 minutes followed by a solution of 70-amino-3- (1-pyridinylethyl) -3-cephem-4-carboxylate in chloroform, slurried with 5.8 g of the cephem compound dichloride salt in 45 ml of chloroform. It was prepared by adding 7 ml of N, O-bis (trimethylsilyl) -acetamide at -30 to -10 ° C. The reaction mixture was stirred at the same temperature for 30 minutes and then evaporated to dryness in vacuo. To the residue was added 100 ml of 80% aqueous formic acid and the aqueous mixture was stirred for one hour at room temperature. Water (110 mL) was added and the insoluble precipitate was filtered off. The filtrate was washed with ethyl acetate and evaporated to dryness in vacuo. The resulting residue was dissolved in water and subjected to column chromatography on a nonionic polymeric resin of Dianion HP-20 (registered trademark, Mitsubishi Chemical Industries Ltd., Japan). The column was washed with water and eluted with 20% aqueous methanol. Fractions containing the cephalosporin compound were combined and evaporated to dryness in vacuo. Acetone is added to the residue and the precipitate is filtered off. 2/22 g of 70 - [(Z) -2- (2-amino-thiazol-4-yl) -2 - [(2-pyrrolo) oxo] -3-oxyimino] -acetamide] -3 1- (1-pyridinomethyl) -3-cephcm-4-carboxylate (1-isotncr) is obtained. Another name for the rotary isomer is 70. [(Z) -2- (2-Aminololiazol-4-yl) -2 - ((3S) -2-pyrrolidone-3-yl) oximino] -acetamido] -3- (1-) pyridiniomethyl / 3-cephem-4-carboxylate,

NMR (D 6 O) δ: 2.2-2.7 (2H, m), 3.1-3.8 (4H, m), 5.05 (1H, t, J = 7Hz), 5.28 (1H , d, J = 5Hz). 5.36 (1H, d, J = 14Hz), 5.63 (1H, d, J = 14Hz), 5.87 (1H, d, J = 5Hz), 6.98 (1H, s), δ, 10 (2II, t, J = 7.5Hz), 8.57 (1H, t, J = 7.5Hz),

8.98 (1H, d, J = 7.5Hz). [a] ² ° D = -38.0 ° (C = 1, H ₂ O).

Example 7 A mixture of sodium iodide (g) and water (4 ml) was stirred at 80 ° C, followed by pyridine (3.6 g) and 70 - [(Z) -2- / 2-aminothiazol-4-yl] -2- [ (2-Pyrrolidid-3-yl) -oximino] -acetamido] -cephalosporinic acid was added and the reaction mixture was stirred at 75-80 ° C for one hour. The reaction mixture was cooled and poured into 150 ml of water and evaporated to dryness in vacuo. The residue was dissolved in 150 ml of water and the solution was adjusted to 1 with 2N hydrochloric acid. The insoluble precipitate is filtered off. the filtrate was washed with ethyl acetate, adjusted to pH 6 with 2N sodium hydroxide, and concentrated in vacuo to 30 ml. The resulting solution was subjected to column chromatography on a non-ionic polymer resin Dianion HP-20 (registered trademark of Mitsubishi Chemical Industries Ltd., Japan). The column was washed with water and eluted with 20% aqueous methanol. Fractions containing the cephalosporin compound were collected and evaporated to dryness in vacuo. Acetone was added to the residue and the powder was filtered off. 0.67 g of 70 - [(2 S) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolo) idon-3-yl] oximino] acetamido] -3- [1-pyridinyl] methyl-3-cephem-4-carboxylate is obtained.

The product has the same physico-chemical characteristics as the product obtained in Example 4.

Example 8

1. 1.5 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2 - [(1-methyl-2-pyrrolidon-3-yl) -oximino] -acetic acid is dissolved in 50 ml of tetrahydrofuran. then 1.4 g of benzhydryl-70-amino-3 - [(dimethyl-1 H -tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylate, 0.6 g of 1-hydroxybenzotriazole and 0.92 g dicyclohexylcarbodiimide is added. After stirring for 2 hours at room temperature, the reaction mixture was worked up according to the procedure of Example 3 (1).

1.58 g of benzhydryl-70 - [(Z) -2- [2- [trityl-amino] -thiazol-4-yl] -2 - [(1-methyl-2-pyrrolidon-3-yl) -oximino] -acetamido} -3 / l-methyl-1H-tetrazol-5-yl / thiomethyl / -3-cephem-4-carboxylate s ^zu NMR (CDC1 ₃₎ δ: 2.2-2.6 (2H ^ n), 2.75 (3H , s), 3.1 -

3.5 (2H, m), 3.5-3.8 (2H, m), 3.84 (3H, s), 4.2-4.4 (2H, m), 4.8-5.2 ( 2H, m), 5.8-6.1 (1H, m), 6.72 (1H, s),

6.90 (1H, s), 7.0-7.5 (25H, m), 8.5-8.8 (2H, broad).

OC

2. To a mixture of 1.5 ml of anisole and 10 ml of trifluoroacetic acid is added 1.5 g of benzhydryl-70 - [/ Z / -2- [2- / trityl-amino / thiazol-4-yl] -2 - [/ methyl 2-pyrrolidon-3-yl] oximino] acetamido] -3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylate and the mixture was stirred for 30 minutes. After stirring in vacuo to remove the trifluoroacetic acid, ether was added and the precipitate was filtered off, slurried in 15 ml of water and added with sodium hydrogencarbonate to dissolve the solution in ethyl acetate and wash with ethyl acetate.

Amberlite XAD-2 (registered trademark of Rohm and Haas Co., HSA) was subjected to column chromatography on a nonionic polymer resin. Water is used as the eluent. Fractions containing the cephalosporin compound were combined and evaporated to dryness in vacuo. 0.61 g of sodium 70 ^{4 'J} [/ Z / -2- / 2-aminothiazol-4-ji / -2 - [/ l - obtained the novel compound - 2 - pyrrolidone-3-yl / oxyimino] acetamido] 3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate is obtained.

NMR (D ₂ O) δ: 2.1 - 2.7 (2H.m). 2.89 (3H, s), 3.2-3.8 (4H, m), 4.05 (3H, s), 4.05-4.3 (2H, m), 4.9-5, 3 (2H; n), 5.73 (1H, d, J = 5Hz), 7.00 (1Hs).

Example 9

1. 0.5 g of (Z) -2- [2- (trityl-anino) -thiazol-4-yl] -2 - (2-piperidin-3-yl) oximino] -actamidoacetic acid is dissolved in 10 ml of tetrahydrofuran and 0.47 g of benzhydryl. -70-amino-3 - [(1-methyl-1 H -tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylate, 0.15 g of 1-hydroxybenzotriazole and 0.24 g of dicyclohexylcarbodiimide. After stirring for 2.5 hours at room temperature, the reaction mixture was worked up according to the procedure of Example 3, point 1. 0.47 g of benzhydryl-70 - [/ Z / -2- [2-trityl-amino] - thiazol4-yl] -2 - [(2-piperidin-3-yl) -oximino] -acetamido] -3- [1-methyl-α-tetrazol-5-yl] -thiomelyl] -3-cephe ] 4-carboxylate is obtained.

NMR _(DMSO-D) δ: 2.00-2.5 (4H, m), 3.0-3.3 (2H, m), 3.6-3.8 (2H, m), 3, Δ (3H, s), 4.1-4.3 (2H.m),

4.6-4.8 (1H, m), 4.9-5.4 (1H, m), 5.85 (1H.d, d, J = 8Hz, J = 5Hz), 6.71 (1H, s) ), 6.81 (1H, s), 7.0-7.6 (26H, m),

9.63 (1H, d, J = 9Hz).

188,937

2. To a mixture of 10 ml of trifluoroacetic acid and 8 ml of anisole is added 0.4 g of benzhydryl-7 / F [/ Z / -2- [2- (trityl) amino) thiazol-4-yl] -2- f / 2 - piperidone-3-yl-oximino] -acetamido] 3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -3-cefcm4-carboxylate and allowed to stand at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to remove trifluoroacetic acid. Ether was added to the residue and the powder was filtered off. The precipitate was suspended in water and sodium bicarbonate was added to dissolve. The solution was washed with ethyl acetate and subjected to column chromatography on Amberite XAD-2 (registered trademark of Rohm and Haas Co., USA) using a nonionic polymer resin. The column was washed with water and eluted with 10% aqueous methanol. Fractions containing the cephalosporin compound were combined and evaporated to dryness in vacuo. 0.9 g of sodium 7/3 - [(Z / -2 / 2-aminothiazol-4-yl) -2 - [(2-piperidin-3-yl) oximino] acetamide] - 3 - [ 1- (methyl-1H-tetrazol-5-yl / thiomethyl) -3-cephem-4-carboxylate is obtained.

NMR (D ₂ O) δ: 1.5-2.3 (4H, m), 3.0-3.4 (2H, m),

3.4-3.6 (2H, m), 3.90 (3H, m), 4.0-4.2 (2H, m), 5.03 (1H, d, J = 5Hz), δ, 63 (1H, d, J = 5Hz), 5.85 (1H, s).

Example 10

1. 18.2 g of phosphorus oxychloride are added dropwise to 9.2 ml of dimethylformamide under ice-cooling and the mixture is stirred at 25-35 ° C for 30 minutes. After cooling to 0 ° C, 100 ml of chloroform was added, followed by further cooling to -35 ° C. 20 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) -oximino] -acetic acid are added dropwise at -35 to 25 ° C. (I-isomer) and triethylamine (5.6 ml) in dimethylformamide (160 ml) were stirred at the same temperature for a further 20 minutes. A mixture of 16 g of 7-amino-cephalosporinic acid, 48 g of trimethylchlorosilane in 35.6 ml of pyridine in 160 ml of Ν, Ν-dinethylacetamide is stirred at 10-20 ° C for 2 hours to give 7-amino- a solution of cephalosporinic acid is prepared. It is added dropwise to the reaction mixture at -35 to 20 ° C with stirring. The mixture was stirred for another 20 minutes at the same temperature and then poured into 2 L of ice water with vigorous stirring. The crystalline precipitate was filtered off, washed with water, ethyl acetate and ether and dried in vacuo. 26.5 g of 7β - [(Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) -oximino] -acetamido] -cephalosporinic acid are obtained. (1-isomer) as a colorless powder.

NMR _(DMSO-d6) δ: 2.06 (3H, s), 2.1-2.5 (2H, m);

3.1-3.4 (2Hpn), 3.45 (1H, d, J = 18Hz), 3.75 (1H, d, J = 18Hz), 4.6-5.02 (3H, m), 5.17 (1H, d, J = 5Hz), 5.6-5.9 (1H, m), 6.81 (1H, s), 7.1-7.6 (15H, m), 7 , 97 (1H, s), 8.88 (1H, broad s), 9.64 (III, d, J = 6Hz).

2. To a mixture of water (18 ml) and dimethylformamide (18 ml) was added sodium iodide (67.5 g) and pyridine (10.9 g) and the mixture was heated to 80 ° C. Then 11.5 g of 7/3 - [N - [[2- (trityl-amino) -thiazol-4-yl] -2 - [[2-pyrrolidone-3-yl] -oxynino] -acetamido] -cephalosporinic acid (1-isomer) was added and the mixture was stirred at 80 ° C for 35 minutes. After cooling, ice water (90 mL) was added to the reaction mixture and washed with ethyl acetate. The reaction mixture was then concentrated in vacuo to remove ethyl acetate and adjusted to pH 2 with 10% hydrochloric acid. The crystalline precipitate is filtered off, washed with water and dried in vacuo. 11.9 g of 70 - [(Z) -2- [2- (tritylamino) -thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) -oximino] -acetamidoy -3- / 1 - pyridinomethyl-3-cephem 4-carboxylate (1-isomer) was obtained as a crude pale yellow powder.

3. 5.5 g of 7 (3 - [(Z) -2 - [- trityl-aminophthiazol-4-yl] -2 - [[2-pyrrolidone-3-yl] oximino] acetamide) were obtained. - (1-Pyridinomethyl) -3-cephem-4-carboxylate (1-isomer) was dissolved in 90 ml of 80% formic acid and the solution was stirred at room temperature for 1 hour, and 200 ml of water were evaporated in vacuo. The insoluble precipitate was filtered off, the aqueous filtrate was washed with ethyl acetate, then concentrated in vacuo to remove the ethyl acetate and applied to a column containing 200 ml of a nonionic adsorption resin (Diaion HP-20, from Mitsubishi Chemical Industries Ltd.). Elute with 20% aqueous methanol, concentrate in vacuo and add acetone to the residue, filter the resulting powdery precipitate to give 1.6 g of 7β - [(Z) -2- [2-aminothiazol4yl] -2 - [ (2-Pyrrolidone-3-yl-oximino] -acetamido] -3-pyrimidinomethyl-3-cephcm4-carboxylate (1-isomer) is obtained in the form of a pale yellow powder. self.

The product has the same physico-chemical properties as: a

Example 6.

Example 11

2.5 g of 7 (3 - [(Z / 2- (1-tritylamino) -thiazol-4-yl) -2 - [[2-pyrrolidone 3-yl]) were prepared according to Example 10, paragraph 1. Oximino] -acetamido] -cephalosporinic acid (1 isomer) is dissolved in 50 ml of 80% formic acid and the solution is stirred for 1 hour at room temperature, and the insoluble precipitate is filtered off, the filtrate is evaporated in vacuo and water is added. The aqueous mixture was then washed with ethyl acetate and evaporated in vacuo to a column containing 200 ml of a nonionic adsorption resin (Dianion HP-20) which was washed with water and treated as described in Example 10.3. g of sodium 7 (3 - [(Z) -2- / 2-aminothiazol-4-yl] -2 - [[2-pyrrolidon-3-yl] oximino] acetamido] cephalosporanate (1-isomer) is obtained. also known as sodium-7R - [(Z) -2- (2-aminothiazol-4-yl) -2] - [3S] -2-pyrrolidone-3-oximino] -acetanedio cephalosporanate.

NMR (υ, Ο) δ: 2.12 (3H, s), 2.3-2.6 (2H, m), 3.2-3.9 (411, m), 4.75 (III, d) , J = 13Hz), 4.95 (1H, d, J = 13Hz), 5.10 (1H, t, J = 7Hz), 5.25 (1H, d, J = 5Hz), 5.85 (1H) , d, J = 5Hz), 7.08 (1H, s).

The products thus obtained were reacted according to the procedure of Example 7 to give 70 - [(Z / -2- / 2-aminothiazol-4-yl) -2 - [(2-pyrrolidone-3-yl) oximino] acetamido] -3 1- (1-pyridinomethyl) -3-cephem-4-carboxylate (1-isomer) is obtained.

Example 12

960 mg 7) 3 - [(N - [2- (2-Amino-thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) -oximino] -acetamido] -cephalosporinic acid, 730 ml of isonic acid, A mixture of 4.5 g of sodium iodide in 3 ml of water was stirred at 65-70 ° C for 6 hours and

-9188 937 was cooled and water (20 mL) was added. The insoluble precipitate was filtered off and the filtrate was applied to a column containing 100 ml of nonionic adsorption resin (Dianion HP-20). The column was washed with water and eluted with 20% aqueous methanol. The eluate was evaporated in vacuo and 175 mg of 7β - [(Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oximino] acetamido] -3- [4- ( Carbamoyl -1-pyridinium methyl-3-cefcm4-carboxylate is obtained as a pale yellow powder.

163-166 ° C (dec.).

NMR (CF ₃ CO ₂ C) δ: 2.5-3.0 (2H, m), 3.5-4.0 (4H, m),

5.2-5.5 (3H, m), 5.5-5.8 (1H, m), 5.9-6.2 (1H, m), 7.35 (1H, s), δ, 4-8.7 (2H, m), 9.1-9.4 (2H, in).

Example 13

960 mg of 7 (3 - [(2R-2-amino-thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) -oximino] -acetamido] -cephalosporinic acid, 650 mg of 4-hydroxy -methyl-pyridine, 4.5 g of sodium iodide and 3 ml of water were stirred at 65-70 ° C for 7 hours and worked up as described in Example 12. 150 mg of 7 (3 - [/ Z / - 2 - / 2-amino-thiazol-4-yl / -2 - [[2-pyrrolidone-3-yl] -oximino] -acetamido] -3- [4- (hydroxymethyl / -1-pyridinium-methyl] -3-cephem 4-Carboxylate is obtained as a pale yellow powder.

162-184 ° C (dec.).

NMR (D ₂ O) δ: 2.3-2.7 (2 μη), 3.1-3.7 (4H, m), 4.8-5.0 (2H, m), 5.03 (2H , s), 5.24 (1H, d, J = 5Hz), 5.3 5.6 (1H, m), 5.93 (1H, d, J = 5Hz), 6.81 (1H, s) , 7.8-8.2 (2H, m), 8.6-9.0 (2H, m).

Example 14

960 mg of 7/3 - [(2-amino-thiazol-4-yl) -2 - [(2-pyrrolidone-3-yl) -imino] -acetamido] -cephalosporinic acid, 650 mg of 3-hydroxymethylpyridine A mixture of 4.5 g of sodium iodide and 3 ml of water was reacted according to the procedure of Example 12. 83 mg 7/3 - [/ Z / -2- / 2-amino-thiazol-4-yl] -2 - [/ 2-pyrrolidone-3-11 / oximino] -acetamido] -3 - [3 - / Hydroxymethyl-1-pyridinium-methyl] -3-cephem-4-carboxylate is obtained.

128-135 ° C (dec.).

NMR (D ₂ O) δ: 2.1 - 2.8 (2H, m), 3.1 - 3.8 (4H, m),

4.86 (2H, s), 4.9-5.1 (2H, m), 5.27 (1H, d, J = 5Hz), 5.35.6 (1H, m), 5.83 (1H, d, J = 5Hz), 6.96 (111, s), 7.7-8.2 (1H, m), 8.3-8.6 (1H, m), 8.6-9 , 1 (2 H, m).

Preparation of starting compounds

1. 15.8 g of ethyl N - [2- (2-tritylamino) thiazol-4-yl] -2-hydroxyamino / acetate are dissolved in 70 ml of dimethylsulfoxide and 5.8 g of anhydrous potassium carbonate are added. added. The mixture was stirred for 20 minutes at room temperature and then

6.6 g of 3-bromo-2-pyrrolidone are added. After stirring for 20 minutes at room temperature, the reaction mixture was poured into 800 ml of water and the crystalline precipitate was filtered off and washed with water. The crystals were dissolved in chloroform, washed with water and dried. The chloroform solution was evaporated in vacuo. To the residue was added 100 mL of ethyl acetate and allowed to stand at room temperature. A crystalline precipitate is formed which is filtered off. 16.0 g of ethyl N - [2- (2-trityl-amino-thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oximino] acetate are obtained.

Mp: 209-210 ° C.

NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7Hz), 2.1-2.6 (2H, m), 3.1-3.6 (2H, m), 4.34 ( 2H, q, J = 7Hz), 4.90 (1H, t, J = 7Hz), 6.35 (1H, s), 7.0-7.6 (17H, m).

To a mixture of methanol (160 mL) and aqueous 2N sodium hydroxide (30 mL) was added 16.0 g of ethyl N - [2- (2-tritylamino) thiazon-4-yl] -2 - [[2-pyrrolidone-3-yl]. (- oximino) acetate and refluxed for 30 minutes. After cooling, the precipitated crystalline precipitate is filtered off and washed with methanol. The crystals are suspended in 30 ml of water and the pH of the suspension is adjusted to 3 with 2N hydrochloric acid. The crystalline precipitate was filtered off and dried. 11.4 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) -oximino] -acetic acid are obtained.

150-153 ° C (dec.).

NMR _(DMSO-d6) δ: 1.8-2,4 (2H, m), 2.9-3.4 (2H, m), 4.63 (lH, t, J = 7Hz), 6.76 ( 1H, s), 6.9-7.6 (15H, m), 7.85 (1H, s), 8.70 (1H, broad s).

2. To 100 ml of dioxane containing 10.5 g of methyl L-phenylalaninate is added 30 g of (Z) -2- [2- (thrylamino) thiazol-4-yl] -2 - [[2-pyrrolidone-3]. Il-oximino] -acetic acid and 60 ml of methanol were added and the mixture was heated to 50 ° C to dissolve the precipitate. To the solution was added dioxane (700 mL) and the mixture was stirred at room temperature for 5 hours. The precipitated crystalline precipitate is filtered off (this filtrate is termed filtrate I) and the resulting crude product (14.3 g) is dissolved in methanol (24 mL). To the methanolic solution was added dioxane (280 mL) and the mixture was stirred for 4 hours at room temperature and the precipitated crystalline precipitate was filtered (called filtrate II). 12.2 g (Z) -2- [2- (Trityl-amino) -thiazol-4-yl] -2 - [(2-pyrrolidin-3-yl) oximino] -acetic acid (1 isomer) methyl L-phenylalaninate we get salt.

í «] jj ⁵ = -14.0 ° (C = 1, methanol).

12.2 g of this salt are dissolved in 120 ml of methanol and 176 ml of 0.1 N hydrochloric acid are added. After stirring for 2 hours under ice-cooling, the crystalline precipitate was filtered off and washed with methanol. 7.5 g of (Z--2- [2- (trityl-amino) -thiazol-4-yl] -2 -1/2-pyrrolidone-3-yl) -oxynino] -acetic acid (1-isomer) are obtained. Another name for the rotary isomer; / Z / -2- [2- / tritylamino / -thiazol-4ilj ^ -l / PSJ-l-pyrrolidone-J-III-oximinoj acid.

142-143 ° C (dec.).

[?] D ⁵ = -38.8 ° (C '- 1, dimethylformamide)

3. I and II obtained in accordance with the procedure described in point 2. The filtrate is evaporated to dryness in vacuo, the residue is dissolved in 250 ml of methanol and 450 ml of 0.1 N hydrochloric acid are added dropwise. The mixture was stirred under ice-cooling for 2 hours and the precipitated crystalline precipitate was filtered off. The crystalline material was washed with methanol and dried. 20 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2- (2-pyrrolidon-3-yl) -oximino] -acetic acid (mainly containing the d-isomer) are obtained. 20 g of (Z) -2 - [- (tritylamino) -thiazol-4-yl] -2 - [(2-pyrrolidon-3-yl) -oximino] -acetic acid (20 g) and methanol (40 ml) were added to the reaction mixture (7.0). to 70 ml of dioxane containing methyl D-phenylalaninate (g) and stirred at 50 ° C to dissolve the precipitate. Thereafter, 450 ml of dioxane were added and the mixture was heated at room temperature for 4 hours

Stir at 188,937. The excellent crystalline precipitate was filtered off. The resulting crude product (13.3 g) was dissolved in methanol (20 ml) and dioxane (260 ml) was added and the mixture was stirred at room temperature for 4 hours. The excellent crystalline precipitate was filtered off. 12.0 g of (Z--2- [2- (trityl-amino) -thiazol-4-yl) -2 - [(2-pyrrolidone-3-yl) -oximino] -acetic acid (d-isomer) methyl D- phenylalaninate salt is obtained.

[α] ^ ⁵ = + 13.9 ° (C = 1, methanol).

The above salt (12.0 g) was dissolved in methanol (120 ml) and 0.1 N hydrochloric acid (174 ml) was added and the mixture was stirred under ice-cooling for 2 hours. The precipitated crystalline precipitate was filtered off and washed with methanol. 7.3 g of (Z--2- [2- (tritylamino) -thiazol-4-yl] -2 - [(2-pyrrolidone-3-yl) oximino] -acetic acid (d-isomer) are obtained. Another name for the dextrorotatory isomer is: N- [2- (2-Trityl-amino) -thiazol-4-yl] -2 - [(3R) -2-pyrrolidon-3-yl] -oximino] -acetic acid.

M.p. 143-144 ° C (dec.).

[Α] D ²⁵ + 37.4 ° (C = 1, dimethylformamide).

4. Dissolve 2.7 g of ethyl 2 - [(2-trityl-amino) -thiazol-4-yl] -2 - [(hydroxyimino) - acetate in 12 ml of dimethyl sulfoxide and 1.0 g of anhydrous potassium carbonate is added to the solution under nitrogen. After stirring for 10 minutes at room temperature, 1.2 g of 1-methyl-3-bromo-2-pyrrolidone are added and the mixture is stirred for 5 hours at room temperature. The reaction mixture was then poured into water (100 mL) and the precipitated crystalline precipitate was filtered off. The crystalline material was dissolved in ethyl acetate and washed with water and dried. The solution was concentrated in vacuo and the residue was crystallized from isopropyl ether and filtered. 2.1 g of ethyl N- [2- [2- (trityl) amino] thiazol-4-yl] -2 - [(1-methyl-2-pyrrolidon-3-yl) oximino] acetate are obtained.

NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7Hz), 2.0-2.7 (2H, m), 2.88 (3H, s), 3.0-3.6 ( 2H, m), 4.34 (2H, q, J = 7Hz), 4.92 (1H, t, J = 7Hz), 6.54 (1H, s), 6.87 (111, s), 7.0-7.5 (15 H, m).

2.7 g of ethyl N- [2- (2-trityl-amino-thiazol-4-yl) -2 - [(1-methyl-2-pyrrolidon-3-yl) -oximino] -acetate are suspended in 27 ml. methanol and 4.9 ml of 2N sodium hydroxide are added. The mixture was refluxed for 20 minutes, cooled, and concentrated in vacuo to remove methanol. The residue was adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated in vacuo. The residue was then crystallized with ether and the crystals were filtered off. 2.15 g of (Z) -2- [2- (tritylamino) thiazol-4-yl] -2 - [(1-methyl-2-pyrrolidone-3-yl) oxirnino] acetic acid are obtained.

142-145 ° C (dec.).

NMR _(DMSO-d6) δ: 2.0 -2.5 (2H, m), 2.77 (3ii, s);

3.1-3.4 (2H, m), 4.78 (1H, t, J = 8Hz), 6.87 (111, s), 6.97.5 (Kill.m).

5. Dissolve 1.3 g of (Z) -2- [2- (trityl-amino) -thiazol-4-yl] -2-hydroxyimino-acetic acid in 10 ml of dimethylformamide and

Sodium hydride (0.24 g, 60% oily dispersion) was added, and the mixture was stirred at room temperature for 15 minutes. Then 3-bromo-2-piperidone (0.65 g) was added and stirred at room temperature for 1.5 hours. The reaction mixture was poured into water and washed with ethyl acetate-tetrahydrofuran (1: 1), the pH of the aqueous phase was adjusted to 3 with 10% hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1: 1), dried and evaporated to dryness in vacuo. ether was added and the resulting precipitated precipitate was filtered off, and the powder (1.3 g) was purified by chromatography on silica gel (eluent: methanol: chloroform, 1: 4) 0.85 g / Z / -2- [2- / trityl-amino] N-thiazol-4-yl] -2 - [(2-piperidin-3-yl) -oximino] -acetic acid is obtained.

145-150 ° C (dec.).

Claims (10)

Claims A process for the preparation of 7/3 - [(Z) -2- (2-aminothiazol-4-yl) -2-oximinoacetamido] -3-cephem-4-caronic acid derivatives of formula I and their pharmaceutically acceptable salts. where R ¹ is hydrogen or lower alkyl; R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio; and R ³ is carboxy; obsession R ² is a group of Formula IX; R ³ is carboxylate and Y is hydrogen, hydroxymethyl or carbamoyl; and n is 2 or 3, characterized in that a) i) condensing a compound of formula II wherein R ⁴ is a protecting group, R ¹ and n are as defined above, or a reactive derivative thereof with a compound of formula III or a salt thereof, wherein R ⁵ is a carboxy group or a protected a carboxy group when R ² is an acetoxy group or a (1-ethyl-1H-ctarazol-5-yl) thio group; or R ⁵ is a -CO 2 - group when R ² is a group of formula IX and Y is as defined above and the compound of formula (IV) thus obtained, almi R ¹ , R ² , R ⁴ , R ⁵ and n are as defined above, (i) deprotecting the protecting group (s), and (iii) optionally converting it into a pharmaceutically acceptable salt, or (b) the. (la) for the preparation of 7/3 - [(Z) -2- (2-aminothiazol-4-yl) -2-oximinoacetamido] -3-cephem-4-carboxylic acid derivatives and their pharmaceutically acceptable salts, where R ¹ is hydrogen or lower alkyl; R ⁶ is (1-methyl-lH-tetraz.ol-5-yl) thio, and R ³ represents karboxiesoport: or R ⁶ (IX) wherein; R ³ is - COO and Y is hydrogen, hydroxymethyl or carbamoyl; cs n is 2 or 3, (i) reacting a compound of formula (V) or a salt thereof, wherein R ⁷ is hydrogen or a protecting group, and R ¹ and n are as defined above, with a pyridine compound of formula (X); wherein Y is as defined above, or (1-methyl-5-mercaptoj-tetrazole or a salt thereof, (ii) when R ⁷ is a protecting group, deprotecting and (iii) optionally converting the product into a pharmaceutically acceptable salt. -11188,937 A process for the preparation of a compound of formula (I) according to claim 1 wherein in formula (I) R ¹ is hydrogen or methyl; R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio and R ³ is carboxy; or R ² is a group (IX), and R ³ is -COO ^- and Y is hydrogen, hydroxymethyl or carbamoyl group; n is 2 or 3, characterized in that the compounds of the general formulas (II) and (III), (V) and (X) are the starting materials where R ¹ , R ² , R ³ , Y and na are as defined above and R indicated ^4, R ⁶ and R ⁷ in the first claim. A process for the preparation of a compound of formula (I) according to claim 1 wherein R ¹ is hydrogen or methyl; R ² is (1-methyl-1H-tetrazol-5-yl) thio, and R ³ is carboxy; or R ² is a group of formula IX and R ³ is a carboxylate group and Y is a hydrogen atom, 4-hydroxymethyl group, 3-hydroxymethyl group or 4-carbamoyl group, and n is 2 or 3, characterized in that , starting from compounds of formulas II and III, V and X, wherein R ¹ , R ² , R ³ , Y and na are as defined above, and R ⁴ , R ⁶ and R ⁷ are As claimed in claim 1. A process for the preparation of a compound of formula (I) according to claim 1, wherein R ¹ is hydrogen, R ² is (IX), R ³ is carboxylate and Y is hydrogen. a hydroxymethyl group, a 3-hydroxymethyl group or a 4-carbamoyl group, and n is 2, characterized in that the compounds of the formulas (II) and (III) and (V) and (X) wherein R ¹ , R ² , R ³ , Y and na are as defined above and R ⁴ , R ⁶ and R ^{7 are} as defined in claim 1. The process according to claim 4, wherein 70 - [(Z) -2- (2-amino-thiazol-4-yl) -2 - [(2-pyrrolidone-3-yl) -oximino] -acetamido] -3- (1-pyridinylmethyl) -3- [alpha] -cm-4-carboxylate or a pharmaceutically acceptable salt thereof, characterized in that (Z) -2- [2- (trityl-anino) thiazol-4-yl] -2 - [( 2-pyrrolidone-3-yl) oximino] acetic acid and 7β-amino-3- (1-pyridinomethyl) -3-cephem-4-carboxylate, and 7β (1 - [(Z) -2- (2-amino) thiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oximino] acetamido] -3- (acetoxymethyl) -3-cephem-4-carboxylic acid is used as starting material. 6. The process according to claim 5, which is 70 - [(Z) -2- (2-aminothiazol-4-yl) -2 - [(3 S) -2-pyrrolidon-3-yl) oximino] - acetamido] -3- (1-pyridinylmethyl) -3-cefcm4-carboxylate or a pharmaceutically acceptable salt thereof, characterized in that (Z) -2 - [- (tritylamino) thiazol-4-yl] -2 [ (2-Pyrrolidone-3-yl) oximino] -acetic acid is prepared from the 1-isomer and 7- (3-amino-3- (1-pyridinomethyl) -3-cephem-4-carboxylate). 7. A process for the preparation of a pharmaceutical composition, 10, characterized in that Figs. 7) 3 - [(Z) -2- (2-Aminothiazol-4-yl) -2-oximinoacetamido] -3-cephem 4-carboxylic acid or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, where R ¹ is hydrogen or lower alkyl; R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio; and R ³ is carboxy, or 20 ^R2 (IX) wherein; R ³ is - COO and Y is hydrogen, hydroxymethyl or carbamoyl, and n is 2 or 3, Mixed with 25 pharmaceutically acceptable carriers. 8. A process according to claim 7 wherein R * is hydrogen, R ² is (IX). 30, R ³ is carboxylate, Y is hydrogen, 4-hydroxymethyl, 3-hydroxymethyl or 4-carbamoyl, and n is 2. The method of claim 7, wherein 35 that the active ingredient was 7β - [(Z) -2- (2-aminothiazol-4-yl) -2 - [(2-pyrrolidon-3-yl) oximino] acetamido] -3- (1-pyridinium) il) -3-cephein-4-carboxylate or a pharmaceutically acceptable salt thereof. The process of claim 7, wherein 40 that the active ingredient was 7 (3 - [(Z) -242-aminothiazol-4-yl) -2 - [(2Z-2-pyrrolidon-3-yl) oximino] acetamide; - 3- (.beta.-pyridinylmethyl) -3-cephem-4-carboxylate or a pharmaceutically acceptable salt thereof.